A method for detecting additives in polyvinyl chloride solid medicinal hard tablets

Abstract

The present invention belongs to the technical field of analysis and detection, and specifically relates to a method for detecting additives in polyvinyl chloride solid pharmaceutical hard tablets. The detection method of the present invention comprises the following steps: preparing a test solution and a mixed standard solution containing additives, and performing detection by HPLC, wherein the chromatographic column is C 18 Chromatographic column; A in the mobile phase is 0.1% formic acid aqueous solution, and B is methanol; the additives include 9 ultraviolet absorbers, 3 antioxidants and 5 plasticizers. The present invention establishes a method for simultaneously detecting 17 additives (including 9 ultraviolet absorbers, 3 antioxidants and 5 plasticizers) in polyvinyl chloride solid pharmaceutical hard tablets by optimizing the extraction method and chromatographic separation conditions, and uses it in the detection of actual samples, which not only reduces the analysis cost, but also improves the detection efficiency, provides convenience for the analysis of large quantities of samples, and can provide technical support for the analysis of additives in plastic hard tablets.

Description

Technical Field

[0001] The invention belongs to the technical field of analysis and detection, and in particular relates to a method for detecting additives in a polyvinyl chloride solid medicinal hard tablet. Background Art

[0002] Polyvinyl chloride (PVC) solid pharmaceutical hard sheets are the base materials for pharmaceutical blister packaging, and are mainly used for the packaging of capsules, tablets, pills and other preparations. PVC hard sheets are made of polyvinyl chloride resins. During production, additives such as UV absorbers, antioxidants and plasticizers that delay the oxidation and decomposition of the resin are often added to improve the processing and use performance of the product. During the contact between the packaging and the drug, these additives may migrate into the drug, affecting the safety of the drug. Existing research results show that phenolic antioxidants have weak estrogenic effects, which can accumulate in the human body and interfere with the human endocrine system, threatening human health; benzotriazole UV absorbers have certain physiological toxicity and bioaccumulation, which can lead to imbalances in the thyroid system and fatty acid metabolism; phthalate esters (PAEs) plasticizers are environmental hormones that can interfere with the balance of human hormones and affect normal growth and development. The European Union, the United States and other countries have listed PAEs as priority controlled pollutants. my country's "Standard for the Use of Additives in Food Contact Materials and Articles" GB9685-2016 and the EU Food Contact Plastics Regulation EU10 / 2011 both regulate additives such as UV absorbers, antioxidants and plasticizers in food contact plastics, and stipulate the types of additives allowed and the usage limits.

[0003] At present, there are many research reports on the detection of additives such as ultraviolet absorbers. Commonly used methods include high performance liquid chromatography, liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry, etc. Most of the studies focus on the detection of single-category compounds. For example, Lu Suya et al. used high performance liquid chromatography to simultaneously determine 9 benzophenone ultraviolet absorbers in cosmetics, and Yu Qiuling et al. used ultra-high performance liquid chromatography-tandem mass spectrometry to screen antioxidants in pharmaceutical rubber plugs. However, the additives in polyvinyl chloride solid pharmaceutical hard tablets are not limited to ultraviolet absorbers and antioxidants, but also plasticizers, and the types of additives are diverse. If they are to be determined one by one, the existing detection methods need to be completed in multiple times, and the method is complicated. Therefore, it is necessary to develop a method that can simultaneously determine 17 additives in polyvinyl chloride solid pharmaceutical hard tablets. Summary of the invention

[0004] In view of the shortcomings of the prior art, the present invention provides a method for detecting additives in polyvinyl chloride solid medicinal hard tablets. The method optimizes the extraction method and chromatographic separation conditions, establishes an HPLC method for simultaneously determining 17 additives (including 9 ultraviolet absorbers, 3 antioxidants and 5 plasticizers) in polyvinyl chloride solid medicinal hard tablets, and uses the method in the detection of actual samples.

[0005] The present invention provides a method for detecting additives in polyvinyl chloride solid pharmaceutical hard tablets, comprising preparing a test solution and a mixed standard solution containing additives, and adopting HPLC method for detection, wherein the chromatographic column is C 18 Chromatographic column; mobile phase A is 0.1% formic acid aqueous solution, and B is methanol;

[0006] The additives include 9 ultraviolet absorbers, 3 antioxidants and 5 plasticizers.

[0007] The present invention adopts HPLC method to detect 17 kinds of components including ultraviolet absorber, antioxidant and plasticizer in polyvinyl chloride solid pharmaceutical hard tablet. The 17 kinds of components to be detected are non-polar or weakly polar organic compounds. Therefore, a reverse phase chromatographic column widely used in liquid phase is selected, and C-18 silane chemically bonded silica gel is used as the stationary phase. 18 The chromatographic column is used for separation. 18 The physical properties of the fillers, such as carbon content, silanization coverage, bonding technology, and silanol tailing groups, are different. Even with the same fillers and columns of the same specifications, the chromatographic retention behavior will be different. Titank C 18 The column can achieve complete separation of 17 components to be tested, with sharp and symmetrical peaks. 18 Specifically, Titank C 18 The model of the chromatographic column is 250mm×4.6mm, 5μm.

[0008] In addition, the composition of the mobile phase has a significant effect on the chromatographic peak shape and separation effect of the compounds to be tested. 18 Commonly used organic mobile phases for chromatographic columns are methanol and acetonitrile. The inventors previously investigated the separation effects of the two mobile phases and found that there was basically no difference in the results. Considering cost and environmental pollution, methanol is used as the organic mobile phase and a small amount of formic acid is added to the mobile phase to improve the tailing of the chromatographic peak and provide a better peak shape for the compounds to be tested. Therefore, the present invention selects methanol-0.1% formic acid water as the mobile phase.

[0009] Preferably, in the above technical scheme, the preparation method of the mixed standard solution is: accurately weigh about 50 mg of each additive standard substance in a 50 mL brown volumetric flask, dissolve and dilute to the scale with acetonitrile to prepare a mixed standard stock solution in which the concentration of each additive is 1000 mg / L; accurately pipette an appropriate amount of the prepared mixed standard stock solution and dilute it with acetonitrile to form a mixed standard solution.

[0010] Preferably, in the above technical scheme, the preparation method of the test solution is: take an appropriate amount of the test sample, cut it into pieces of 0.2 cm×0.2 cm, mix it and accurately weigh it, put it in a stoppered conical flask, add acetonitrile, seal it, weigh it, ultrasonicate it for 30 to 40 minutes, cool it, weigh it again, make up the lost mass with acetonitrile, shake it evenly, filter it with a 0.22μm microporous filter membrane, and the filtrate is the test solution.

[0011] Preferably, in the above technical solution, the power of the ultrasound is 350-450W, and the frequency is 40kHz; the preferred power is 350W.

[0012] Ultrasonic power and ultrasonic time are one of the main factors affecting the extraction efficiency of the components to be tested. Increasing ultrasonic power and extending ultrasonic time can promote the dissolution of the components to be tested, but if the ultrasonic power is too large, the large number of cavitations produced may reduce the transfer of energy by reflecting sound waves, thereby reducing the penetration of the extraction solvent and reducing the dissolution efficiency of the test object. At the same time, the high energy and long-term extraction of ultrasound increase the thermal effect, which may cause the degradation or isomerization of the components to be tested. The inventor found in preliminary experiments that when the ultrasonic frequency is 40kHz, the recovery rate of each component gradually increases with the increase of ultrasonic power. When the power reaches 350W, the recovery rate tends to balance. Therefore, 350W is preferably used as the sample ultrasonic power; and ultrasound for 30min can achieve full extraction, with a recovery rate of more than 86%. If the ultrasonic time is continued to increase, the recovery rate does not change significantly. Therefore, the preferred ultrasonic time is 30min.

[0013] Preferably, in the above technical scheme, during HPLC detection, gradient elution is performed, and the program is: 0-17 min, 60% B-85% B; 17-27 min, 85% B; 27-43 min, 85% B-100% B; 43-54 min, 100% B; 54-55 min, 100% B-60% B; 55-60 min, 60% B.

[0014] Preferably, in the above technical scheme, the ultraviolet absorber is UV-0, UV-24, UV-9, UV-71, UV531, UV329, UV326, UV234, UV327; the antioxidant is antioxidant 2246, antioxidant 425, antioxidant 3114; the plasticizer is DMP, DEP, BBP, DEHP, DNOP.

[0015] Preferably, in the above technical solution, when HPLC detects plasticizers, the wavelength is 245nm; when detecting antioxidants, the wavelength is 280nm; when detecting ultraviolet absorbers, the wavelength is 290nm.

[0016] The inventors previously conducted full wavelength scanning of 17 additives to be tested within the wavelength range of 190-800nm, and obtained characteristic absorption peaks of the 17 additives at different wavelengths. Each additive has a high sensitivity at 203nm, but the chromatographic baseline is not stable and is easily interfered by impurities. Therefore, combined with the detection sensitivity and interference of each additive, the detection wavelengths of plasticizers, antioxidants, and ultraviolet absorbers were selected to be 245nm, 280nm, and 290nm, respectively.

[0017] Preferably, in the above technical solution, during HPLC detection, the flow rate is 1.0 mL / min.

[0018] Preferably, in the above technical solution, during HPLC detection, the injection volume is 20 μL.

[0019] Preferably, in the above technical solution, during HPLC detection, the column temperature is 25-30°C.

[0020] Advantages compared to the prior art:

[0021] 1. The present invention uses ultrasonic extraction combined with high performance liquid chromatography technology to optimize the sample pretreatment conditions and chromatographic analysis conditions, and verifies the linearity, recovery rate, stability and other parameters of the method, and establishes a method for simultaneously detecting the contents of 17 additives in polyvinyl chloride solid pharmaceutical hard tablets, which can be used for the detection of actual samples;

[0022] 2. The present invention has simple pretreatment, good linear relationship, accuracy, repeatability and stability, and uses different detection wavelengths to improve the analytical sensitivity of each component. It can simultaneously measure ultraviolet absorbers, antioxidants and plasticizers, reducing the detection cost, while saving sample processing and analysis time, improving detection efficiency, and providing convenience for large-scale sample analysis. It is suitable for the detection of 17 additives in polyvinyl chloride solid medicinal hard tablets and can provide technical support for the analysis of additives in plastic hard tablets. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is the chromatogram of Example 1 of the present invention;

[0024] Figure 2 It is the chromatogram of Example 2 of the present invention;

[0025] Figure 3 The figure is a diagram showing the extraction effects of different extraction solvents on 17 additives of the present invention;

[0026] Figure 4 is the blank solvent acetonitrile chromatogram;

[0027] Figure 5 It is the chromatogram of Comparative Example 1 of the present invention;

[0028] Figure 6 It is the chromatogram of Comparative Example 2 of the present invention;

[0029] Figure 7 It is the chromatogram of Comparative Example 3 of the present invention;

[0030] Figure 8 It is the chromatogram of Comparative Example 4 of the present invention;

[0031] Fig. 9 It is the chromatogram of Comparative Example 5 of the present invention;

[0032] Fig.10 It is the chromatogram of Comparative Example 6 of the present invention;

[0033] Fig.11 It is the chromatogram of Comparative Example 7 of the present invention;

[0034] Fig.12 It is the chromatogram of Comparative Example 8 of the present invention;

[0035] Fig.13 It is the chromatogram of Comparative Example 9 of the present invention;

[0036] Fig.14 This is the chromatogram of sample No. 16 in the sample detection of the present invention.

[0037] Among them, peak 1 is DMP, peak 2 is DEP, peak 3 is UV-0, peak 4 is UV-24, peak 5 is UV-9, peak 6 is BBP, peak 7 is UV-71, peak 8 is antioxidant 2246, peak 9 is antioxidant 425, peak 10 is UV531, peak 11 is DEHP, peak 12 is UV329, peak 13 is DNOP, peak 14 is antioxidant 3114, peak 15 is UV326, peak 16 is UV234, and peak 17 is UV327. DETAILED DESCRIPTION

[0038] The above-mentioned technical features of the present invention and the technical features specifically described below (such as implementation cases) can be combined with each other to form new or preferred technical solutions, but the present invention is not limited to these embodiments, and these embodiments do not limit the present invention in any way.

[0039] The experimental methods in the following examples are conventional methods unless otherwise specified. The reagents involved in the following examples are common commercial products and can be purchased from the market unless otherwise specified.

[0040] The present invention is further described in detail below in conjunction with the drawings and embodiments:

[0041] 1. Main Materials

[0042] 19 batches of polyvinyl chloride solid pharmaceutical hard tablets (numbered 1-19) were sourced from 6 pharmaceutical packaging material manufacturers; the standard product information is shown in Table 1; methanol and acetonitrile, chromatographic grade, were from Sigma-Aldrich, USA; formic acid, analytical grade, was from Xilong Scientific Co., Ltd.

[0043] Table 1 Standard product information

[0044]

[0045]

[0046] 2. Instruments and equipment

[0047] High performance liquid chromatograph, LC-20ADXR, equipped with SPD-M20A two-stage array tube detector, Shimadzu Corporation, Japan; ultrasonic cleaner, KQ 500DE, Kunshan Ultrasonic Instrument Co., Ltd.; ultrapure water analyzer, Elix Essential, Merck Millipore, Germany.

[0048] 3. Solution Preparation

[0049] 3.1 Preparation of mixed standard solution

[0050] Accurately weigh about 50 mg of each of the 17 additive standard substances into a 50 mL brown volumetric flask, dissolve in acetonitrile and dilute to scale to prepare a mixed standard stock solution with a concentration of 1000 mg / L for each additive;

[0051] Accurately pipette an appropriate amount of the mixed standard stock solution and dilute it with acetonitrile to form a mixed standard solution with a concentration of 100 μg / mL for each additive.

[0052] Accurately pipette an appropriate amount of the mixed standard stock solution and dilute it step by step with acetonitrile to prepare a series of linear mixed standard solutions with the concentration of each additive being 0.5, 1, 2, 5, 10, 25, and 50 μg / mL.

[0053] 3.2 Preparation of single standard solution

[0054] Accurately weigh about 10 mg of each of the 17 additive standard substances, place them in different volumetric flasks, and add acetonitrile to dilute them into a single standard solution with a concentration of 100 μg / mL.

[0055] 3.3 Preparation of test solution

[0056] Take an appropriate amount of sample, cut it into pieces of 0.2cm×0.2cm, mix it, take out 2g, weigh it accurately, put it in a stoppered conical flask, add 10mL of acetonitrile, stopper it, weigh it, ultrasonicate (power 350W, frequency 40kHz) for 30min, let it cool, weigh it again, make up the lost mass with acetonitrile, shake it evenly, filter it with a 0.22μm microporous filter membrane, and take the filtrate.

[0057] Example 1

[0058] A method for detecting additives in polyvinyl chloride solid pharmaceutical hard tablets comprises the following steps: taking a mixed standard solution with a concentration of 100 μg / mL, and detecting it by HPLC, and the chromatographic conditions are as follows:

[0059] Column: Titank C 18 Chromatographic column (250 mm × 4.6 mm, 5 μm);

[0060] Mobile phase: A is 0.1% formic acid aqueous solution, B is methanol;

[0061] Gradient elution program: 0-17 min, 60% B-85% B; 17-27 min, 85% B; 27-43 min, 85% B-100% B; 43-54 min, 100% B; 54-55 min, 100% B-60% B; 55-60 min, 60% B;

[0062] Flow rate: 1.0 mL / min;

[0063] Detection wavelength: plasticizer is 245nm; antioxidant is 280nm; UV absorber is 290nm;

[0064] Injection volume: 20 μL;

[0065] Column temperature: 30℃.

[0066] Record the chromatogram. Figure 1 shown.

[0067] Example 2

[0068] A method for detecting additives in polyvinyl chloride solid pharmaceutical hard tablets comprises the following steps: taking a mixed standard solution with a concentration of 100 μg / mL, and detecting it by HPLC, and the chromatographic conditions are as follows:

[0069] Column: Titank C 18 Chromatographic column (250 mm × 4.6 mm, 5 μm);

[0070] Mobile phase: A is 0.1% formic acid aqueous solution, B is methanol;

[0071] Gradient elution program: 0-17 min, 60% B-85% B; 17-27 min, 85% B; 27-43 min, 85% B-100% B; 43-54 min, 100% B; 54-55 min, 100% B-60% B; 55-60 min, 60% B;

[0072] Flow rate: 1.0 mL / min;

[0073] Detection wavelength: plasticizer is 245nm; antioxidant is 280nm; UV absorber is 290nm;

[0074] Injection volume: 20 μL;

[0075] Column temperature: 25℃.

[0076] Record the chromatogram. Figure 2 shown.

[0077] Example 3

[0078] Acetonitrile was used as the extraction solvent. The sample solution was prepared according to the method of preparing the test solution in 3.3. The samples with 17 kinds of additive standard solutions were tested according to the chromatographic conditions of Example 1. The extraction effect was as follows: Figure 3 At the same time, the blank solvent acetonitrile was tested using the same detection method, and its chromatogram is shown in Figure 4 shown.

[0079] Comparative Example 1

[0080] A method for detecting additives in polyvinyl chloride solid pharmaceutical tablets, the difference is that ZORBAX EdipseXDB C 18 Chromatographic column, other detection methods are the same as in Example 1, record the chromatogram, the chromatogram is as follows Figure 5 shown.

[0081] Comparative Example 2

[0082] A method for detecting additives in polyvinyl chloride solid pharmaceutical tablets, the difference is that the method uses SunFire C 18 Chromatographic column, other detection methods are the same as in Example 1, record the chromatogram, the chromatogram is as follows Figure 6 shown.

[0083] Comparative Example 3

[0084] A method for detecting additives in polyvinyl chloride solid pharmaceutical hard tablets, the difference is that Kromasil C 18 Chromatographic column, other detection methods are the same as in Example 1, record the chromatogram, the chromatogram is as follows Figure 7 shown.

[0085] Comparative Example 4

[0086] A method for detecting additives in polyvinyl chloride solid pharmaceutical tablets, the difference being that Venusil MP C 18 Chromatographic column, other detection methods are the same as in Example 1, record the chromatogram, the chromatogram is as follows Figure 8 shown.

[0087] Comparative Example 5

[0088] A method for detecting additives in polyvinyl chloride solid pharmaceutical hard tablets, the difference is that a Wondasil C18Superb chromatographic column is used, and other detection methods are the same as those in Example 1, and a chromatogram is recorded. The chromatogram is as follows: Fig. 9 shown.

[0089] Comparative Example 6

[0090] A method for detecting additives in polyvinyl chloride solid pharmaceutical hard tablets, the difference is that the gradient elution program is: 0-10min, 70%B-90%B; 10-25min, 90%B; 25-40min, 90%B-100%B; 40-52min, 100%B; 52-53min, 100%B-70%B; 53-58min, 70%B, other detection methods are the same as in Example 1, and the chromatogram is recorded. The chromatogram is as shown in Fig.10 shown.

[0091] Comparative Example 7

[0092] A method for detecting additives in polyvinyl chloride solid pharmaceutical hard tablets, the difference is that the gradient elution program is: 0-17min, 60%B-85%B; 17-27min, 85%B; 27-55min, 85%B-100%B; 55-64min, 100%B; 64-65min, 100%B-60%B; 65-70min, 60%B, other detection methods are the same as in Example 1, and the chromatogram is recorded. The chromatogram is as shown in Fig.11 shown.

[0093] Comparative Example 8

[0094] A method for detecting additives in polyvinyl chloride solid pharmaceutical hard tablets, the difference is that the column temperature is 35°C, the other detection methods are the same as in Example 1, and the chromatogram is recorded. Fig.12 shown.

[0095] Comparative Example 9

[0096] A method for detecting additives in polyvinyl chloride solid pharmaceutical hard tablets, the difference is that the column temperature is 40°C, the other detection methods are the same as in Example 1, and the chromatogram is recorded. The chromatogram is as follows Fig.13 shown.

[0097] Comparative Example 10

[0098] Methanol was used as the extraction solvent, and the sample solution was prepared according to the test solution preparation method in 3.3. The samples with 17 kinds of additive standard solutions were tested according to the chromatographic conditions in Example 1. The extraction effect was as follows: Figure 3 shown.

[0099] in conclusion:

[0100] It can be seen from the chromatograms of Examples 1 and 2 that the chromatographic conditions of the present invention can simultaneously detect 17 additives in polyvinyl chloride solid pharmaceutical hard tablets with good separation, high sensitivity, fast speed and high detection efficiency.

[0101] Comparative Example 1 and Comparative Examples 1 to 5, Titank C was used in Example 1. 18 The column can achieve complete separation of 17 components to be tested, with sharp and symmetrical peaks; while Comparative Examples 1 to 5 use ZORBAX Edipse XDB, SunFire, Kromasil, Venusil MP, and Wondasil C18 Superb, with specifications of 250mm×4.6mm and 5μm C 18 When the chromatographic columns were used to separate 17 additives, some chromatographic peaks overlapped, and the separation effect was poor. For the ZORBAX column and SunFire column, the chromatographic peaks of DEHP and UV329, UV326 and UV234 completely overlapped, and only 15 chromatographic peaks were separated.

[0102] Comparative Example 1 and Comparative Examples 6 to 7, in Comparative Example 6, a high proportion of methanol is used. Although the analysis time of each analyte can be shortened, the analyte compounds with fast elution peaks cannot be effectively separated; in Comparative Example 7, the initial proportion of methanol is set to 60%, and the time for gradient elution to 100% methanol is increased. Although the analyte compounds with fast elution peaks are effectively separated, the separation of DEHP and UV329 chromatographic peaks is affected, and the overall analysis time is prolonged.

[0103] Comparing Examples 1-2 and Comparative Examples 8-9, it can be seen from the results of Examples 1-2 that as the column temperature increases, the chromatographic separation time of each additive is correspondingly shortened, and all have good separation, and the peak shape of each chromatographic peak is good; when the column temperature is 35°C in Comparative Example 8, the DEHP and UV329 chromatographic peaks fail to achieve baseline separation; when the column temperature is 40°C in Comparative Example 9, only 16 chromatographic peaks are separated, DEHP and UV329 overlap into one chromatographic peak, and the separation degree of DEP and UV0 is poor. This shows that the higher the temperature of the chromatographic column is, the better the detection is.

[0104] It can be seen from the extraction effect diagram of comparative example 3 and comparative example 10 that in comparative example 10, methanol is used to extract 17 additives, and the extraction recovery rate is 67.82% to 96.85%, wherein the extraction recovery rates of UV234 and UV327 are lower than 75%, and the efficiency of acetonitrile extraction in embodiment 3 is relatively high, with a recovery rate of 86.92% to 105.82%, and the extraction efficiency of UV234 and UV327 is significantly higher, indicating that the extraction efficiency of using acetonitrile as an extraction solvent is better. In addition, it can be seen from the blank acetonitrile chromatogram that using acetonitrile as an extraction solvent does not produce interference peaks, and the effect is good.

[0105] Methodological investigation

[0106] 1. Linear relationship, detection limit and quantification limit

[0107] A series of linear mixed standard solutions were taken for determination, and the determination was carried out according to the chromatographic conditions of Example 1. The peak area of ​​each component to be measured was used as the ordinate (y) and the corresponding mass concentration was used as the abscissa (x, μg / mL) to make a standard curve, and the linear equation of each component to be measured was obtained. The results showed that the 17 additives had a good linear relationship in the range of 0.5 to 50 μg / mL, and the correlation coefficients were all greater than 0.999. The detection limit (LOD, S / N=3) and the quantification limit (LOQ, S / N=10) were calculated based on the concentrations corresponding to the 3-fold signal-to-noise ratio and the 10-fold signal-to-noise ratio of each analyte, which were 0.12 to 0.78 μg / g and 0.24 to 2.61 μg / g, respectively. The results are shown in Table 2.

[0108] 17 kinds of single-label solutions of additives were measured according to the chromatographic conditions in Example 1, the single-label solutions were positioned, and the retention times were recorded. It can be seen from the retention times of the chromatographic peaks of each additive that the retention times did not overlap. The retention times of each additive are shown in Table 2.

[0109] Table 2 Retention time, linear relationship, detection limit and quantification limit of 17 additives

[0110]

[0111] 2. Recovery and Repeatability

[0112] Accurately weigh 2 g of sample (No. 13, DMP is 9.68 μg / g, UV531 is 14.15 μg / g) cut into pieces of 0.2 cm × 0.2 cm, place in a stoppered conical flask, accurately add 10 mL of high (40 μg / mL), medium (10 μg / mL), and low (2.5 μg / mL) concentration mixed standard solutions, prepare 3 samples in parallel for each concentration, seal, weigh, ultrasonically (power 350 W, frequency 40 kHz) for 30 min, cool, and weigh again. The weight was adjusted to 100%, and acetonitrile was used to make up for the lost weight. The mixture was shaken and filtered through a 0.22 μm microporous filter membrane. The filtrate was taken to obtain the test solution for recovery and repeatability test. The test was carried out according to the chromatographic conditions in Example 1. The recovery and relative deviation (RSD) were calculated. The test results are shown in Tables 3 and 4. From the results in Tables 3 and 4, it can be seen that the average recovery of 17 additives was 88.45% to 103.87%, and the RSD% was 1.21% to 3.78%, indicating that the method has good accuracy and repeatability.

[0113] Table 3 Average recovery and repeatability of 17 additives (n=9)

[0114]

[0115]

[0116]

[0117]

[0118] Table 4 Summary of recovery and repeatability test results of 17 additives (n=9)

[0119]

[0120] 3. Solution stability

[0121] The test solution spiked with 10 μg / mL in the recovery test was taken and placed at room temperature for 0, 1, 2, 4, 8, 12, 16, and 24 hours, and then sampled and measured according to the chromatographic conditions in Example 1. The results showed that the RSDs of the peak areas of the 17 additives were 0.65% to 1.92% (n=8), indicating that each additive was stable after being placed at room temperature for 24 hours.

[0122] Test example

[0123] According to the chromatographic conditions of Example 1, the 19 batches of samples collected were prepared according to the test solution preparation method in 3.3 and then measured. The content of additives in the samples was calculated by the standard curve method. The measurement results are shown in Table 5. The results show that 4 additives were detected, namely plasticizer DMP, ultraviolet absorbers UV531, UV329, and UV234, and the remaining 13 additives were not detected. Among them, UV531 was detected in 18 batches of samples, with a detection rate of 94.74% and a content of 1.41-14.15μg / g. UV329 was detected in 5 batches of samples, with a content of 0.54-1.13μg / g. DMP and UV234 were detected in 2 batches of samples, with contents of 5.64-9.68μg / g and 1.24-2.59μg / g, respectively. Among them, the chromatogram of sample No. 16 is shown in the figure below. Fig.14 shown.

[0124] Table 5 Sample measurement results (μg / g)

[0125] Sample No. DMP UV531 UV329 UV234 1 - 5.65 0.95 - 2 - 7.06 1.13 - 3 - - 0.62 - 4 - 3.71 - - 5 - 5.26 - - 6 - 4.22 - - 7 - 3.78 - - 8 - 4.86 - - 9 - 5.27 - - 10 - 1.41 - - 11 - 4.82 - - 12 - 4.25 - - 13 9.68 14.15 - - 14 - 4.73 - 1.24 15 5.64 4.84 - 2.59 16 - 3.61 - - 17 - 4.64 0.54 - 18 - 4.90 - - 19 - 4.90 0.62 -

[0126] Note: “-” means not detected.

[0127] In summary, the present invention adopts ultrasonic extraction combined with high performance liquid chromatography technology to optimize the sample pretreatment conditions and chromatographic analysis conditions, and establishes a method for simultaneously detecting the contents of 17 additives in polyvinyl chloride solid medicinal hard tablets. The determination method has good linearity, accuracy, repeatability and stability, and can simultaneously determine ultraviolet absorbers, antioxidants and plasticizers, thereby reducing the detection cost, saving sample processing and analysis time, improving the detection efficiency, providing convenience for large-scale sample analysis, and being suitable for the detection of 17 additives in polyvinyl chloride solid medicinal hard tablets, and can provide technical support for the analysis of additives in plastic hard tablets.

[0128] Finally, it should be emphasized that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various changes and modifications. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for detecting additives in polyvinyl chloride solid pharmaceutical hard tablets, characterized in that: The test solution and the mixed standard solution containing additives were prepared and detected by HPLC, wherein the chromatographic column was a Titank C18 column with a specification of 250 mm × 4.6 mm and 5 μm; the mobile phase A was a 0.1% formic acid aqueous solution and B was methanol; The additives include 9 kinds of ultraviolet absorbers, 3 kinds of antioxidants and 5 kinds of plasticizers; the ultraviolet absorbers are UV-0, UV-24, UV-9, UV-71, UV531, UV329, UV326, UV234 and UV327; the antioxidants are antioxidant 2246, antioxidant 425 and antioxidant 3114; the plasticizers are DMP, DEP, BBP, DEHP and DNOP; During HPLC detection, gradient elution was performed with the following program: 0-17 min, 60% B-85% B; 17-27 min, 85% B; 27-43 min, 85% B-100% B; 43-54 min, 100% B; 54-55 min, 100% B-60% B; 55-60 min, 60% B.

2. A method for detecting additives in polyvinyl chloride solid pharmaceutical hard tablets according to claim 1, characterized in that: The preparation method of the mixed standard solution is: accurately weigh about 50 mg of each additive standard substance in a 50 mL brown volumetric flask, dissolve and dilute to the scale with acetonitrile to prepare a mixed standard stock solution with a concentration of each additive of 1000 mg / L; accurately pipette an appropriate amount of the prepared mixed standard stock solution and dilute it with acetonitrile to form a mixed standard solution.

3. A method for detecting additives in polyvinyl chloride solid pharmaceutical hard tablets according to claim 1, characterized in that: The preparation method of the test solution is as follows: take an appropriate amount of the test sample, cut it into pieces of 0.2 cm×0.2 cm, mix it and accurately weigh it, put it in a stoppered conical flask, add acetonitrile, seal it, weigh it, ultrasonicate it for 30 to 40 minutes, let it cool, weigh it again, make up the lost mass with acetonitrile, shake it evenly, filter it with a 0.22μm microporous filter membrane, and the filtrate is the test solution.

4. A method for detecting additives in polyvinyl chloride solid pharmaceutical hard tablets according to claim 3, characterized in that: The power of the ultrasound is 350-450W, and the frequency is 40kHz.

5. The method for detecting additives in polyvinyl chloride solid pharmaceutical hard tablets according to claim 1, characterized in that: When HPLC detects plasticizers, the wavelength is 245 nm; when detecting antioxidants, the wavelength is 280 nm; when detecting UV absorbers, the wavelength is 290 nm.

6. The method for detecting additives in polyvinyl chloride solid pharmaceutical hard tablets according to claim 1, characterized in that: During HPLC detection, the flow rate was 1.0 mL / min.

7. A method for detecting additives in polyvinyl chloride solid pharmaceutical hard tablets according to claim 1, characterized in that: For HPLC detection, the injection volume was 20 μL.

8. The method for detecting additives in polyvinyl chloride solid pharmaceutical hard tablets according to claim 1, characterized in that: During HPLC detection, the column temperature was 25-30°C.

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